The presence of essential metals in sufficient quantities and in a biologically available form in diet is essential for maintaining the health and well being of domestic animals and poultry. Because essential metals such as copper, iron, manganese and zinc are often deficient in common feed ingredients, supplemental amounts of these nutrients are often added to the feed of domesticated animals and poultry. Many commercial feed additives have been developed to provide the essential metals in forms that are readily biologically utilizable. The degree of biological availability of nutrients is often referred to as “bioavailability”. Bioavailability of essential metals depends on the physical and/or chemical properties of the form in which the metal is present in the diet. Increased bioavailability of supplemental metals is beneficial because it allows the use of lower concentrations of the metals in the diet to meet the nutritional needs of animals, while lowering the potential harmful effects of high levels of these metals both on the animals and on the environment.
Several commercial products are available in which trace elements are more bioavailable than the corresponding inorganic source of the metal. The enhanced bioavailability is attributed to the association of the metal with an organic molecule, generally known as ligand. This association or bonding results in the increased availability of the metal for utilization by animals, i.e. increased bioavailability. The increased bioavailability of the essential elements in these products is the result of increased solubility, greater stability in the gut, enhanced absorption into circulation and/or improved metabolic utilization.
Different types of products that contain a trace element associated with an organic ligand are commercially available. These can be classified in different groups based on the nature of the ligand used in manufacturing the product. In one class of products, amino acids are used as the ligands that form complexes or chelates with the metal. Examples of these products are described in U.S. Pat. Nos. 3,941,818; 3,950,372; 4,067,994; 4,863,898 4,900,561; 4,948,594; 4,956,188; 5,061,815; 5,278,329; 5,583,243; and 6,166,071. A second group of feed additives include the metal salts of short chain carboxylic acids such as propionic acid (See U.S. Pat. Nos. 5,591,878, 5,707,679, 5,795,615 and 5,846,581). A third group of trace element additives is classified by the American Feed Control Officials as Metal Proteinate and defined as “the product resulting from the chelation of a soluble salt with amino acids and/or partially hydrolyzed protein”. Examples of these products are described in U.S. Pat. Nos. 3,440,054, 3,463,858, 3,775,132, 3,969,540, 4,020,158, 4,076,803, 4,103,003, 4,172,072 and 5,698,724.
The common assignee of the present application has in the past synthesized and patented metal complexes of amino acids as a more bioavailable source of the essential elements. The following are examples of these patents: U.S. Pat. Nos. 3,941,818; 3,950,372; 4,021,569; 4,039,681; and 4,067,994 disclose 1:1 complexes of alpha amino acids, preferably DL-methionine with the transition metals zinc, chromium, manganese and iron. The formation of similar complexes with L-methionine is disclosed in U.S. Pat. No. 5,278,329. U.S. Pat. Nos. 4,900,561 and 4,948,594 disclose copper complexes of alpha amino acids containing terminal amino groups. Complexes of copper, manganese, zinc and iron with alpha hydroxyl aliphatic carboxylic acids are disclosed in U.S. Pat. Nos. 4,956,188 and 5,583,243. U.S. Pat. Nos. 4,670,269 and 4,678,854 disclose complexes of cobalt with poly-hydroxy carboxylic acid such as glucoheptanoic acid. Complexes of the amino acid L-lysine with trace elements are disclosed in U.S. Pat. No. 5,061,815. The effectiveness of the compounds disclosed in these patents has been demonstrated from data provided in some of these patents and in numerous scientific publications and technical reports.
The above patents describe the use of pure synthetic or natural amino or hydroxyl acids. In U.S. Pat. No. 5,698,724 the assignee of the current application disclosed the synthesis of complexes of essential elements with natural amino acids obtained by the hydrolysis of proteins. Since this patent was issued, a large number of field studies have demonstrated that metals from these complexes are more bioavailable than metals from inorganic sources.
Based on our experience with metal-amino acid complexes as described in the references cited above, we have concluded that the 1:1 complexes of the metals Zn, Mn, Cu, Co, Fe are effective nutritional sources of the metals and more advantageous than the 1:2 complexes. These 1:1 complexes exist as ion pairs in which the metal-amino acid comprises the cation. The counter ion (anion) is provided by a mineral acid and is necessary for balancing the charge on the cation. The requirement for the external anion results in products in which the metal content is limited. The purpose of the present invention is to develop metal amino acid complexes in which the amino acid serves a dual role. It serves as the bidentate ligand to form a complex with the metal ion, and the counter ion to balance the charge on the cationic complex. This allows the preparation of stable crystalline complexes that contain 20–30% metal. The alpha amino dicarboxylic acids aspartic and glutamic acids are examples of suitable ligands that meet these requirements.
A careful review of the patent and scientific literature indicated that some sources make reference to compounds containing metals and aspartic or glutamic acid. However, it is not always clear what complexes are being described and what is the relevance of this prior art to the intended use of these complexes in nutrition contemplated in the present invention. Two scientific reports were published in 1966 describing the crystal structures of copper glutamate dihydrate and zinc glutamate dihydrate. In the first report copper glutamate dihydrate was obtained by the slow evaporation of a solution of glutamic acid and copper nitrate (The Crystal Structure of Copper Glutamate Dihydrate, Carlo M. Gramaccioli and Richard E. Marsh, Acta Cryst., 21, 594 (1966)) The structure of the blue-green crystals was determined by x-ray crystallography. A companion paper reported the structure of the zinc glutamate dihydrate crystals obtained by the evaporation of an aqueous solution of zinc oxide in glutamic acid (The Crystal Structure of Zinc Glutamate Dihydrate, Carlo M. Gramaccioli, Acta Cryst., 21, 600 (1966)).
Several salts of aspartic acid and glutamic acid with alkali metals such as sodium, potassium, calcium and magnesium are commercially available. Magnesium aspartate containing 17–20% magnesium and calcium aspartate containing 20% calcium are commercially available and are likely the neutral salts containing one magnesium or calcium cation neutralized by one dibasic anion of aspartic acid. Calcium and zinc acid salts of aspartic and glutamic acids that contain one dibasic cation and two molecules of the dibasic acids are commercially available.
Magnesium aspartate is included among organic salts of magnesium used for the treatment or prophylaxis of auto immune diseases in the text and claims of U.S. Pat. No. 6,248,368 B1. However, magnesium pyrophosphate is singled out as the preferred magnesium salt according to this invention. A method and composition for treatment of headache using magnesium salts are described in U.S. Pat. No. 6,218,192 B1. Although magnesium aspartate and magnesium aspartate hydrochloride appeared among magnesium salts mentioned in the text, the focus appeared to be the administration of water soluble magnesium salts, specifically magnesium sulfate and magnesium chloride. U.S. Pat. No. 6,210,690 B1 describes a water-in-oil type emulsified composition for use in skin and hair cosmetics. These emulsions are stabilized by different additives including salts of amino acids. Although magnesium aspartate and magnesium and calcium glutamates were included among the possible amino acid salts listed in the text, only sodium glutamate was listed in the claims. A flavor blend for masking the unpleasant taste of zinc compounds is disclosed in U.S. Pat. No. 6,169,118 B 1. In the text of this patent the inventors mention zinc aspartate as one of the examples of zinc compounds that may benefit from the teachings of the invention.
The texts of two related patents teach that magnesium aspartate hydrochloride may be used as one of the electrolytes in an antemortem nutrient supplement for livestock (U.S. Pat. Nos. 5,505,968 and 5,728,675). U.S. Pat. No. 5,401,770 describes zinc complexes of natural alpha-amino acids as antipruritic agents. In these complexes the molar ratio of the amino acid to zinc is 2:1. A microbicidal composition obtained by combining under acidic conditions of equimolar amounts of a metal salt, an amino acid and an inorganic acid is described in U.S. Pat. No. 6,242,009 B1. Among the metal salts listed are those of silver, zinc, copper, mercury, chromium, manganese, nickel, cadmium, arsenic, cobalt, aluminum, lead, selenium, platinum, gold, titanium, tin or their combinations. As well, glutamic and aspartic acids are among amino acids listed. A cure for common cold containing a highly ionizable zinc compound is described in U.S. Pat. No. 5,409,905. The inventor states that zinc complexes such as zinc citrate, zinc aspartate and zinc amino acid chelates are too tightly bound at pH 7.4 to release sufficient zinc ions to be useful and are outside the scope of the invention.
A number of U.S. patents make reference to metal salts of glutamic and aspartic acids in conjunction with other inventions. U.S. Pat. No. 2,810,754 describes the use of the copper glutamate complex as an intermediate in the preparation of glutamine from glutamic acid. The recovery of glutamic acid from solutions containing it by precipitation of zinc glutamate salts is described in U.S. Pat. No. 2,849,468. U.S. Pat. No. 4,167,564 describes a method for improving the stability of amino acid-metal complexes containing 2–16 moles of the amino acid per one mole of metal by incorporating in the mixture a buffer system that controls the pH of the complex and its surrounding media. Amino acid chelates consisting of a metal ion chelated to one or more ligands and are essentially free of anion radicals other than hydroxyl and anions of weak organic acids are described in U.S. Pat. No. 4,599,152. A method for the production of ferrous monoglutamate by reacting in aqueous solution a ferrous salt with a glutamic acid material is described in U.S. Pat. No. 3,168,541. An improved diet for fur-bearing animals such as mink is described in U.S. Pat. No. 3,911,117. The diet contains raw marine fish and a chelate of ferric iron with an organic acid. However, the exact chemical nature of the ferric ion chelate with the organic acids is not described.
Two related U.S. patents describe a hair treatment composition to improve the delivery of amino acids to the hair and scalp by forming a “particulate metal-amino acid complex” the metals described in the patent included zinc (U.S. Pat. No. 5,911,978 and U.S. Pat. No. 6,228,353). The text and claims of these patents list 9 amino acids including glutamic acid. However, the examples in both patents use cystine, a sulfur amino acid that contains two carboxyl and two alpha amino groups. The zinc complex formed with cystine is vastly different than that formed between zinc and glutamic acid. U.S. Pat. No. 5,348,749 describes the use of metal-amino acid complexes among other substances for the treatment of panic disorders. Zinc salts of glutamic and aspartic acids containing two molecules of the amino acid per one zinc ion are among the compounds described in this patent.
None of the above described references, have any specific description of neutral complexes of dicarboxylic acids, such as aspartic and glutamic in which the amino acid serves a dual role as the bidentate ligand that forms a complex with the trace mineral metal ion and as the counter ion to balance the charge of the cationic complex. It is, therefore, a primary object of this invention to provide such neutral complexes in a stable form that provide 20%–30% by weight metal.
Another object is to provide nutritional supplements for animal/poultry feed that contain these neutral complexes.
Yet another objective is to provide a method of nutritional supplementation of animals and poultry that provides bioavailable trace minerals, and amino acids without any significant pollution risk.
And, a yet further object is to provide an efficient and economical process of making the complexes of this invention.
The method and manner of accomplishing these and other objectives will become apparent from the written description which follows.